http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/123 2026-04-03T19:28:22Z 2026-04-03T19:28:22Z Chih-Wan Lin 林芝琬 http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54051 2021-06-16T02:38:03Z 2015-01-01T00:00:00Z

標題: 高風險藥物與急性住院：病例─時間─對照研究; High-Risk Medications and Emergency Hospitalizations: A Case–Time–Control Study 作者: Chih-Wan Lin; 林芝琬 摘要: 研究背景 藥物不良事件會惡化病人的健康情況，也會為有限的醫療資源帶來沉重的負擔，若能有效率地找出可能導致嚴重藥物不良事件(如：藥物不良事件引起之住院)的高風險藥物，將有助臨床工作者與政策制定者針對此議題進行改善。過去研究探討不同藥物相關之住院風險此一議題時，多採用分析自動通報紀錄、病歷回顧、以及從病歷資料庫中篩選藥物不良反應相關之診斷碼等方式進行，然而這些方式普遍存在通報不足的問題且各個藥物不良反應之特性會影響通報率；此外，多數研究僅呈現藥物引起之住院事件數而未考慮藥物在整體族群之使用盛行率。 研究目的 為解決上述的研究限制，本研究使用臺灣全民健康保險研究資料庫為資料來源，以病例─時間─對照設計 (case–time–control design) 探討高風險藥物和急性住院事件之間的相關性。 研究方法 由2000年承保抽樣歸人檔中選取年滿20歲且2000年1月1日至2011年12月31日至少有一筆門診處方紀錄者為研究族群。於研究族群中篩選出急性住院事件為index visits而門診就醫事件為reference visits，並將index visits與reference visits以性別、年齡、index date (定義為index 及reference visits 的首日)、Charlson Comorbidity Index、門診次數進行1:1配對。Index visits與reference visits之病例期定為index date 前1-14天，對照期則定為index date 前366-379天，再比較高風險藥物分別在病例期與對照期之暴露情形，本研究選定的高風險藥物為diabetic agents、diuretics、nonsteroidal anti-inflammatory drugs (NSAIDs)、anticoagulants、antiplatelets、antihypertensives、 antiarrhythmics、anticonvulsants、antipsychotics、antidepressants、benzodiazepine (BZD)/Z-hypnotics以及narcotics。統計分析使用條件式邏輯迴歸模型進行odds ratio (OR)的預測，並校正隨時間改變之干擾因子 (包含病例期和對照期之Charlson Comorbidity Index、門診就診次數、急診就診次數、慢性用藥總數)，另計算急性住院事件中與高風險藥物相關之可歸因風險 (attributable fraction (AF))。 研究結果 於12種本研究選定的高風險藥物中，急性住院風險顯著增加者有7種，風險高至低依序為antipsychotics (adjusted OR: 1.54, 95% confidence interval [1.37-1.73], AF: 35.0%)、NSAIDs (1.50, [1.44-1.56], 33.3%)、anticonvulsants (1.34, [1.10-1.64], 25.6%)、diuretics (1.24, [1.15-1.33], 19.1%)、BZD/Z-hypnotics (1.23, [1.16-1.31], 18.8%)、antidepressants (1.17, [1.05-1.31], 14.7%)及antiplatelets (1.16, [1.07-1.26], 14.0%)。anticoagulants、antiarrhythmics、antihypertensives、narcotics與急性住院無顯著之相關性；diabetic agents則顯示保護作用 (0.86, [0.77-0.97])。 以全部急性住院事件進行分析時，使用narcotics之風險增加未達統計顯著，但僅分析住院天數≥10天之急性住院事件時，風險顯著增加。將各個高風險藥物細分為不同子類別進行分析時急性住院風險不同，急性住院風險最高之antipsychotics及NSAIDs中，又以typical antipsychotics及non-selective NSAIDs之風險較高。依年齡分層分析時，antipsychotics、NSAIDs、diuretics、BZD/Z-hypnotics及antiplatelets在<65歲者和≥65歲者之急性住院風險皆顯著增加，anticonvulsants和antidepressants則只在≥65歲者和急性住院有顯著相關性。 研究結論 本研究提供一種全新的「主動監測藥物不良事件」之方式，與現有之被動監測機制互補可提供更完整的資訊，本研究中急性住院風險顯著增加之藥物antipsychotics、NSAIDs、anticonvulsants、diuretics、BZD/Z-hypnotics、antidepressants及antiplatelets等，可作為未來臨床研究與政策執行之目標。; Background: Adverse drug events (ADEs) could threaten the health of the patients and imposed a substantial economic burden on the healthcare system. Therefore, efficient identification of severe ADEs, such as ADE-related hospitalizations, can help highlight area in which improvement of treatment practices clinicians and policy-makers can put efforts in. Previous studies have adopted several approaches to identify ADE-related hospitalizations, such as analysis of spontaneous reporting data, medical chart review, and screening diagnostic codes from electronic medical charts databases. However, these methods were limited by under-reporting and reporting bias. Furthermore, most of the studies only examined the number of ADE-related hospitalizations, and did not consider the prevalence of medication exposure within the population. Objectives: To address the limitations of current approaches, we used a case–time–control design to evaluate the association between high-risk medications and emergency hospitalizations from the National Health Insurance Research Database (NHIRD) in Taiwan. Methods: Using data from the Longitudinal Health Insurance Database (LHID) 2000, patients aged 20 years and over and had received at least one outpatient prescription during 2000 to 2011 were included as our study cohort. Among them, emergency hospitalizations and outpatient visits were identified as index visits and reference visits, respectively. The first date of index and reference visit was defined as the index date. Each index visit was then matched to a randomly selected reference visits by age, gender, index date, Charlson Comorbidity Index and number of outpatient visits. For both index and reference visits, the period of 1-14 days and 366-379 days prior to the index date were defined as case period and control period, respectively. The exposure of high-risk medications during the case period and the control period were then compared. High-risk medications included in our study were diabetic agents, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, antiplatelets, antihypertensives, antiarrhythmics, anticonvulsants, antipsychotics, antidepressants, benzodiazepine (BZD)/Z-hypnotics and narcotics. Conditional logistic regression models were used to estimate odds ratios (ORs) with adjustment for time-varying variables, including Charlson Comorbidity Index, number of outpatient visits, number of emergency visits and number of chronic drugs used. Attributable fractions (AFs) were also calculated to determine the proportion of emergency hospitalizations attributable to exposure of high-risk medications. Results: Overall, antipsychotics (adjusted OR: 1.54, 95% confidence interval [1.37-1.73], AF: 35.0%), NSAIDs (1.50, [1.44-1.56], 33.3%), anticonvulsants (1.34, [1.10-1.64], 25.6%), diuretics (1.24, [1.15-1.33], 19.1%), BZD/Z-hypnotics (1.23, [1.16-1.31], 18.8%), antidepressants (1.17, [1.05-1.31], 14.7%) and antiplatelets (1.16, [1.07-1.26], 14.0%) were significantly associated with increased risks of emergency hospitalizations. Such associations were not found in anticoagulants, narcotics, antiarrhythmics and antihypertensives. Diabetic agents showed protective effect (0.86, [0.77-0.97]). However, when we limited our analyses in emergency hospitalizations with a length of stay ≥10 days, the narcotics significantly associated with an increased risk of emergency hospitalizations. In subgroup analysis by pharmacological properties, typical antipsychotics were associated with higher risks of emergency hospitalizations than atypical antipsychotics. Non-selective NSAIDs was linked with higher risk of emergency hospitalizations than COX-2 selective NSAIDs. Age-stratified analyses showed that antipsychotics, NSAIDs, diuretics, BZD/Z-hypnotics, and antiplatelets were significantly associated with emergency hospitalizations in aged<65 years and aged ≥65 years, but anticonvulsants and antidepressants were associated with increased risk of emergency hospitalizations in the elderly (age ≥65 years) only. Conclusion: This study provides an alternative approach for active pharmacovigilance, which may complement the present passive pharmacovigilance system in Taiwan. Future research can focus on medications significantly associated with increased risks of emergency hospitalizations, including antipsychotics, NSAIDs, anticonvulsants, diuretics, BZD/Z-hypnotics, antidepressants and antiplatelets.

2015-01-01T00:00:00Z Yun-Chen Tsao 曹芸甄 http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45915 2021-06-15T04:48:46Z 2010-01-01T00:00:00Z

標題: 高血脂病人其基因多型性與基礎生化值及史達汀效果之影響; Associations of Genetic Polymorphisms with Baseline Profiles and Lipid-Lowering Effects of Statin Therapy 作者: Yun-Chen Tsao; 曹芸甄 摘要: 高血脂病人血中膽固醇及三酸甘油脂 (triglyceride，TG) 過高，易造成動脈硬化、血栓及中風。目前臨床上最廣為使用的降血脂藥─史達汀 (statin) 類藥物，其能抑制HMG-CoA還原酶 (3-hydroxy-3-methylglutaryl-coenzyme A reductase)，進而減少內生性膽固醇合成與增加細胞膜上的低密度膽固醇受體，導致血中總膽固醇 (total cholesterol，TC)、低密度膽固醇 (low-density lipoprotein cholesterol，LDL-c)及三酸甘油脂濃度減少，並使高密度膽固醇 (high-density lipoprotein cholesterol，HDL-c) 濃度增加。但史達汀治療效果仍存在廣大的變異性，而基因多型性可能可解釋部分原因。 本研究共納入209位高血脂病人，使用atorvastatin (ATV) 或 rosuvastatin (RSV) 四週以上，且有治療前後血脂檢驗值供分析，再收集受試者的DNA進行基因型檢定，篩選與血脂生成、運送或代謝有關的基因，例如ABCA1、ABCG5/G8、APOA5、CETP、FDFT1、LDLR等；與史達汀代謝運送有關的基因，如ABCB1、ABCG2、CYP2C9/19、CYP3A5、SLCO1B1等，共24個SNPs，並分析基因多型性對於基礎生化值或ATV及RSV治療效果是否有相關性。另一方面，欲研究目前最強的史達汀類藥物 ─ RSV的降脂效果與安全性，擴大篩選ABCA1、APOA1、APOA5、CETP、LIPC、LPL、PPARA/D/G等48個SNPs，再進一步探討SNPs或單套型與受試者在RSV治療後TC、TG、LDL-c、HDL-c改變百分比、TG/HDL和TC/HDL比值改變量之間的相關性。 在基礎生化值方面，本研究發現7個相關的SNPs，分別為ABCG2 (rs2231142)、APOA5 (rs3135506)、CETP (rs708272、rs17245715、rs12597250)、LDLR (rs5929)、MIA3 (rs17465637)；在與史達汀降血脂效果相關的SNPs方面，本研究找到2個SNPs與ATV降脂效果有相關性，分別是LDLR (rs5925) 與LDLR (rs4508523)。在RSV方面，有4個SNPs與降血脂效果有顯著影響，分別是ABCG2 (rs2231142)、misc (rs501120)、PPARA (rs1800234)、PPARG (rs4684847)。在單套型分析中，本研究發現ABCA1之單套型，受試者若為較不常見的單套型 C-T-G-G-G-A (頻率：7.899%)，其基礎生化值中的總膽固醇與LDL-c濃度比較為常見的兩個單套型 C-T-G-G-G-G (頻率：13.177%)、T-T-G-G-G-A (頻率：12.033%) 高。在給予RSV治療後，TG濃度改變百分比在最不常見的單套型C-T-G-G-G-A中不降反而些微上升 (C-T-G-G-G-G：T-T-G-G-G-A：C-T-G-G-G-A，-23.904±24.623%：-20.192±24.596%：0.4781±37.064%，p value= 0.019)，且在TG/HDL比值改變量中下降最少 (C-T-G-G-G-G：T-T-G-G-G-A：C-T-G-G-G-A，-1.015±1.7793：-0.8910±1.3887：-0.2638±1.4789，p value= 0.016)。 本研究發現某些基因型與受試者的基礎生化值相關，顯示先天遺傳在血脂濃度方面有其重要性，且基因多型性可能影響ATV與RSV的降脂效果，故本研究可提供高血脂病人在心血管疾病危險性之預防與治療上作為參考。結果是否可於更大的台灣人族群中得到驗證，需未來更多進一步之研究。; Elevated blood cholesterol and triglycerides (TGs) are so-called hyperlipidemia and implicated in the development of atherosclerosis with risks for thrombosis, heart attack and stroke. Currently statins become the most widely used lipid-lowering drugs. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis pathway, resulting in the reduction of endogenous cholesterol synthesis and the increase of low-density lipoprotein (LDL) receptors on cell membrane. It accelerates uptake of LDL from blood circulation, reduces the concentrations of LDL-choleterol (LDL-c), total cholesterol (TC) and TG in plasma and upregulates plasma high-density lipoprotein cholesterol (HDL-c). The effect of statins on anti-hyperlipidemia varies among individuals. Recently genetic polymorphisms are concerned as an important contribution to the differential effects. The DNAs of 209 hyperlipidemic individuals treated with atorvastatin (ATV) or rosuvastatin (RSV) 10 mg/day were analyzed for twenty-four single nucleotide polymorphisms (SNPs) within genes related to lipid synthesis, transport and metabolism, such as ABCA1, ABCG5/8, APOA5, CETP, FDFT1, LDLR, and genes related to statin disposition, including ABCB1, ABCG2, CYP2C9/2C19, CYP3A5, SLCO1B1. The polymorphisms were examined for the association with baseline lipid profiles and the lipid-lowering effects of ATV and RSV. To extensively study gene polymorphisms and the efficacy of statins, additional forty-eight SNPs were screened within genes of ABCA1, APOA1, APOA5, CETP, LPL, LIPC and PPARA/D/G in patients treated with RSV. Genetic variations, SNPs and haplotypes were further analyzed in terms of the levels of TC, TG, LDL-c, HDL-c and the ratio of TG/HDL and TC/HDL upon RSV therapy. SNPs ABCG2 (rs2231142), APOA5 (rs3135506), CETP (rs708272, rs17245715, rs12597250), LDLR (rs5929), MIA3 (rs17465637) were associated with baseline lipid profiles. There were 2 SNPs, LDLR (rs5925) and LDLR (rs4508523), associated with ATV treatment. On the other side, SNPs ABCG2 (rs2231142), misc (rs501120), PPARA (rs1800234) and PPARG (rs4684847) were significantly associated with the RSV treatment. In haplotype analysis, higher baseline TC and LDL-c were shown in the individuals with least common haplotype C-T-G-G-G-A (frequency: 7.899%) of ABCA1, compared to those with more common haplotypes C-T-G-G-G-G (frequency: 13.177%) and T-T-G-G-G-A (frequency: 12.033%). After RSV therapy, individuals with C-T-G-G-G-A haplotype showed the least elevation of TG concentration (C-T-G-G-G-G：T-T-G-G-G-A：C-T-G-G-G-A，-23.904±24.623%：-20.192±24.596%：0.4781±37.064%，p value= 0.019) and reduction of TG/HDL ratio (C-T-G-G-G-G：T-T-G-G-G-A：C-T-G-G-G-A，-1.015±1.7793：-0.8910±1.3887：-0.2638±1.4789，p value= 0.016) among three haplotypes. This study showed that genetic polymorphisms may play a role in baseline lipid profiles and the lipid-lowering effect of ATV and RSV. Further studies are needed for validation of the results of this study in a larger Taiwanese population.

2010-01-01T00:00:00Z Szu-Yu Yeh 葉思妤 http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38740 2021-06-13T16:44:14Z 2011-01-01T00:00:00Z

標題: 高血糖影響腎臟上皮 MDCK II細胞中 P-glycoprotein 表現之機轉探討; Effect of hyperglycemia on P-glycoprotein expression in MDCK II cells 作者: Szu-Yu Yeh; 葉思妤 摘要: 糖尿病 (diabetes) 是一種慢性代謝性疾病，會造成全身微循環的障礙，進而引起腎臟方面的病變。P-glycoprotein (P-gp) 大量存在於腎臟中，主要功能是排除其受質及藥物等異質體，與腎臟組織的保護有關。由本實驗室先前西方墨點法與組織免疫染色的結果顯示，不論在第一型糖尿病Non-obese diabetic (NOD) 母鼠或第二型糖尿病New Zealand obese (NZO) 公鼠的腎臟中，P-gp表現量皆明顯下降；因此本實驗將接續先前的實驗結果，探討糖尿病腎臟中P-gp表現下降之調控機制。 在本研究中，使用犬腎小管上皮細胞MDCK II，作為研究腎臟P-gp表現量之體外試驗模型。為探討糖尿病造成腎臟P-gp表現下降之可能的調控機制，MDCK II分別以IL-6、TNF-α、insulin及高濃度葡萄糖處理後，萃取細胞膜蛋白做西方墨點法試驗，觀察P-gp表現量變化的情形。並以定量即時聚合酶鏈鎖反應 (qRT-PCR) 測定P-gp mRNA 表現量。結果顯示，高濃度葡萄糖會誘導活性氧化物 (ROS) 之生成，同時造成P-gp表現顯著下降；而在細胞激素 (IL-6, TNF-α) 和胰島素環境下則未呈現顯著影響。另一方面，ROS也可以造成P-gp表現下降, 並可被抗氧化劑 N-acetylcysteine (NAC) 所抵消。在高濃度葡萄糖環境下給予細胞PKC inhibitor staurosporine (STS)，可抑制高濃度葡萄糖所造成P-gp 表現下降之現象，顯示PKC 的活化參與高濃度葡萄糖對於P-gp的調控。以PKC agonist PMA處理後P-gp 表現下降，然而共同處理NAC 與 PMA後，PMA誘導之P-gp 表現下降並未被NAC反轉。此外，也藉由觀察細胞內細胞核受體PXR、CAR及內皮素 (Endothelin-1, ET) 與P-gp 調控之關連性。實驗結果發現在高濃度葡萄糖處理24小時後，細胞中 PXR及CAR的mRNA 表現量皆顯著上升。另一方面，在PKC agonist PMA環境下處理12小時後，細胞中 PXR及CAR的mRNA 表現量則下降，這些處理皆未造成蛋白質表現量的改變；RT-qPCR分析並未發現MDCK II 細胞上有內皮素受體 ETR-A / B mRNA 的表現 總結上述研究結果，在高濃度葡萄糖環境下P-gp的表現量是顯著下降的。顯示由葡萄糖調節異常所引起的高血糖 (hyperglycemia) 為糖尿病造成腎臟P-gp 表現下降之主要機轉；且其調控P-gp表現量的機轉與ROS之生成以及活化PKC路徑有關。PXR、CAR、ET以及ETR-A / B路徑並未在此調控中扮演角色。然而是否有其他調控因子參與其中仍需做更進一步的探討。; Diabetes mellitus is a chronic metabolic disease and is related to various complications including nephropathy. Diabetic nephropathy is the most common cause of end-stage renal disease. P-glycoprotein (P-gp) is abundant in the kidney and is closely related to the excretion of xenobiotics and drugs. In this regard, P-gp represents a protective mechanism to exclude endogenous and exogenous toxins in the kidney. Our previous study has shown that P-gp expression is significantly lower in the kidney of animals with type 1 diabetes (Non-obese diabetic, NOD females) or type 2 diabetes (New Zealand obese, NZO males). The present study is to investigate the underlying mechanisms regulating P-gp expression in the kidney under diabetic condition Madin-Darby canine kidney (MDCK) type II cells were used as an in vitro model to study the regulation mechanisms of P-gp expression in the kidney under diabetic condition. P-gp protein expression was analyzed by Western blotting under the treatment of IL-6、TNF-α、insulin and glucose. Quantitative polymerase chain reaction (qPCR) was used to detect P-gp mRNA expression. In addition, the changes of intracellular ROS、PXR、CAR and ETR-A / B expressions were measured to evaluate the effect of high glucose condition on P-gp expression. In MDCK cells, P-gp protein and mRNA expression were reduced in the presence of high glucose concentration, while superoxide production was increased. After pro-inflammatory cytokines, IL-6 and TNF-α treatment, P-gp expression did not show any significantly change, as well as after insulin treatment. The reduction of P-gp expression was abolished by the treatment of an antioxidant, N-acetylcysteine (NAC). Treatment with hydrogen peroxide (H2O2) or protein kinase C (PKC) agonist, phorbol myristate acetate (PMA)significantly reduced P-gp expression. On the other hand, NAC could not reverse the reduction of P-gp expression caused by PMA treatment. However, the decrease of P-gp expression after high glucose exposure was abolished by the treatment of a PKC inhibitor, staurosporine. Furthermore, the roles of PXR, CAR and ET (Endothelin-1, ET) on P-gp regulation were investigated. The results showed that PXR and CAR mRNA expression were significantly increased under high glucose condition for 24 hours. On the other hand, PXR and CAR mRNA expression were decreased by the treatment of PKC agonist, PMA, for 12 hours. Except for PXR at 48 hours glucose treatment, in both situations, there are no significantly changes of PXR and CAR protein expression. In terms of endothelin receptor A or B (ETR-A / B), the RT-qPCR analysis did not show the mRNA expression of ETR-A / B expression in MDCK II cells. In conclusion, the expression of P-gp was decreased in MDCK II cells under high glucose condition. The regulatory pathway of P-gp expression under high glucose concentration was associated with reactive oxygen species (ROS) production and then through PKC activation. PXR / CAR, ET and ETR-A /B pathway do not play a role in this regulation. Further studies are required to understand whether there are any other factors involved in regulating P-gp.

2011-01-01T00:00:00Z Yi-Chun Lai 賴怡君 http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38156 2021-06-13T16:27:10Z 2005-01-01T00:00:00Z

標題: 高效液相層析-固相萃取-核磁共振技術之應用： 一、 金新木薑子葉部生物鹼成分之研究 二、 變葉新木薑子葉部黃酮類成分之研究; Applications of LC-SPE-NMR Technique: I. Study on the alkaloids from the leaves of Neolitsea sericea var. aurata II. Study on the flavonoids from the leaves of Neolitsea variabillima 作者: Yi-Chun Lai; 賴怡君 摘要: 本論文以高效液相層析-固相萃取-核磁共振技術應用在植物之化學成分分離及結構鑑定，研究金新木薑子及變葉新木薑子葉部之化學成分。 一、 金新木薑子葉部生物鹼成分之研究 新木薑子屬之樟科植物含有異奎寧生物鹼且有些具有心血管之活性，為了徹底地探討蘭嶼植物金新木薑子 (Neolitsea sericea var. aurata) 葉部所含之生物鹼成分，本實驗以高效液相層析-固相萃取-核磁共振 (HPLC-SPE-NMR)之連結技術做研究。 其葉部酒精萃取物之酚性生物鹼部分被分為氯仿可溶及水可溶兩部分，再分別以HPLC-SPE-NMR技術分析及鑑定，自氯仿可溶部分共得到五個已知之異奎寧生物鹼：laurolitsine (1)、boldine (2)、reticuline (3)、laurotetanine (4) 和actinodaphnine (5)。自水可溶部分共得到九個異奎寧生物鹼：9S,17S-pallidine N-oxide (6)、corytuberine (7)、1S,2S-reticuline N-oxide (8)、6R,6aS-boldine N-oxide (9)、1S,2R-reticuline N-oxide (10)、norisocorydine (11)、1R,2R-juziphine N-oxide (12)、6S,6aS-N-methyllaurotetanine N-oxide (13)及6R,6aS-N-methyllaurotetanine N-oxide (14)。其中化合物6、8、9、13為新化合物，而化合物10、12及14乃首見於新木薑子屬植物；化合物6、8、10、14以半合成方式製備以確認其立體化學結構。本研究亦對alpha或 beta-N-oxide對附近氫核化學位移之影響進行探討，並利用分子動力學模擬之技術探討化合物8和10之立體化學，據此可合理解釋。 二、變葉新木薑子葉部黃酮類成分之研究 本論文第二部分是研究樟科新木薑子屬植物變葉新木薑子(Neolitsea variabillima) 的黃酮類成分。植物葉部的乙醇萃取物經過極性分割後，正丁醇可溶部分先利用薄層層析掃瞄儀 (TLC scanner) 做初步分析，續以膠濾層析 (Sephadex LH-20) 分離，最後利用HPLC-SPE-NMR之連結技術，共分離並鑑定三個黃酮類成分，分別為 (2R,3R)-dihydroquercetin 3-O-rhamnoside (a)、quercetin 3-O-rhamnoside (b) 及kaempferol 3-O-rhamnoside (c)；此三個化合物皆為已知，以樣品a, b及c比對無誤。本研究提供一個快速篩選黃酮類的方法，對天然物之研究大有助益。; This thesis was aimed to apply LC-SPE-NMR hyphenated technique in the isolation and structural elucidation of chemical constituents from two plant materials, i.e. the leaves of Neolitsea sericea var. aurata and Neolitsea variabillima. I. Study on the alkaloids from the leaves of Neolitsea sericea var. aurata Lauraceous plants of the Neolitsea genus have been shown to contain isoquinoline alkaloids, some of which possess cardiovascular effects. This study was aimed to investigate thoroughly the alkaloids present in the leaves of N. sericea (Blume) Koidz. var. aurata Hayata, a Lauraceous plant indigenous to Lanyu island, via the application of LC-SPE-NMR hyphenated technique. The phenolic alkaloids obtained by the general method from the EtOH extract were divided into fractions soluble in water and chloroform. The water and chloroform fractions were then analyzed by LC-SPE-NMR method. From the chloroform fraction, five known isoquinoline alkaloids, i.e. laurolitsine (1), boldine (2), reticuline (3), laurotetanine (4) and actinodaphnine (5) were characterized. From the water fraction, nine isoquinoline alkaloids, i.e. 9S,17S-pallidine N-oxide (6), corytuberine (7), 1S,2S-reticuline N-oxide (8), 6R,6aS-boldine N-oxide (9), 1S,2R-reticuline N-oxide (10), norisocorydine (11), 1R,2R-juziphine N-oxide (12), 6S,6aS-N-methyllaurotetanine N-oxide (13) and 6R,6aS-N-methyllaurotetanine N-oxide (14) were characterized. Among them, compounds 6, 8, 9, 13 are new and compounds 10, 12, 14 are first found in the Neolitsea plants. The structural conformations of compounds 6, 8, 10 and 14 were achieved by comparing their spectral data with those synthetic compounds prepared in this study. The effect of alpha and beta- N-oxidation on the chemical shifts of the adjacent protons was investigated and the stereochemistries of compounds 8 and 10 were rationalized by the assistance of Molecular Dynamics Simulation (MD Simulation) technique. II. Study on the flavonoids from the leaves of Neolitsea variabillima This study was aimed to investigate the flavonoids present in the leaves of Neolitsea variabillima. The EtOH extract was first divided into several fractions by liquid-liquid partitioning. The flavonoids present in the BuOH fraction was further concentrated by Sephadex LH-20 and analyzed by LC-SPE-NMR hyphenated technique. Totally, three flavonoids, i.e. (2R,3R)-dihydroquercetin 3-O-rhamnoside (a), quercetin 3-O-rhamnoside (b) and kaempferol 3-O-rhamnoside (c) were identified. They were confirmed by HPLC analysis spiked with the samples a, b and c. This study provided a method for fast screening of flavonoids.

2005-01-01T00:00:00Z